4,5,13-Prostatrienoic acid derivatives

ABSTRACT

Novel prostaglandin dehydro analogs of the PGE2 and PGF2 series possessing diethylenic unsaturation in the carboxylic acid chain which may be further substituted at C-4, C-6 and/or C-15 by a methyl, ethyl or propyl group, the C-20 nor- or bisnorderivatives, and certain C-20 alkyl derivatives thereof, processes for the production of such compounds and novel and useful intermediates obtained thereby. Also included are the pharmaceutically acceptable, non toxic esters and salts of the carboxylic acid function and the pharmaceutically acceptable, non toxic esters and/or ethers of the secondary hydroxyl groups. These compounds possess prostaglandin-like activities and thus are useful in the treatment of mammals, where prostaglandins are indicated.

United States Patent [1 1 Crabbe et al.

4,5,l3-PROSTATRIENOIC ACID DERIVATIVES Inventors: Pierre Crabbe, Grenoble. France;

John H. Fried. Palo Alto. Calif.

Assignee: Syntex (U.S.A.), Inc., Palo Alto.

Calif.

Filed: June 11, 1973 Appl. No.: 368.983

Related US. Application Data Continuation-impart of Scr. No. 338.325. March 5. I973. abandoned. which is a continuation-impart of Ser. No. 306.414. Nov. l4. I972. abandoned. which is a continuation-in-part of Ser. No. 204.769. Dec. 3.

I971. abandoned.

References Cited UNITED STATES PATENTS Bundy .L 260/5 14 51 Apr. 22, 1975 OTHER PUBLICATIONS Crabbe et al., Chem. Comm. 904. (I972).

Prinmry Examiner-Robert Gerstl Attorney. Agent. or Firm-Gerard A. Blaufarb; Leon Simon; William B. Walker [57] ABSTRACT Novel prostaglandin dehydro analogs of the PGE and PGFZa series possessing diethylenic unsaturation in the carboxylic acid chain which may be further substituted at C-4. C-6 and/or C-l5 by a methyl. ethyl or propyl group, the C-20 noror bisnorderivatives. and certain C20 alkyl derivatives thereof. processes for the production of such compounds and novel and useful intermediates obtained thereby. Also included are the pharmaceutically acceptable. non toxic esters and salts of the carboxylic acid function and the pharmaceutically acceptable. non toxic esters and/or ethers of the secondary hydroxyl groups. These compounds possess prostaglandin-like activities and thus are useful in the treatment of mammals. where prostaglandins are indicated.

86 Claims, No Drawings 1 4,5,13-PROSTATRIENOIC ACID DERIVATIVES CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of our application Ser. No. 338,325, filed Mar. 5, 1973 which in turn is a continuation-in-part of application Ser. No. 306,414, filed Nov. 14, 1972, a continuation-impart of application Ser. No. 204,769, filed Dec. 3, 1971, all now abandoned and the above applications are herewith incorporated by reference and made a part hereof.

DESCRIPTION OF THE INVENTION The present invention relates to certain novel prostaglandin derivatives, to a process for the production thereof and to certain novel intermediates obtained by this process.

More particularly, the present invention relates to prosta-4,5,13-trans-trienoic acid derivatives having oxygenated functions at C-9 and C-l5 or at C-9, C-11 and C-l5 positions of the molecule, which may be further substituted at C-4, C-6 and/or C-1 5 by a methyl, ethyl or propyl group, to the C-20 norand bisnorderivatives thereof or the C-20-alkyl derivatives thereof, the alkyl group being of a straight chain and containing from 1 to 5 carbon atoms inclusive. Also encompassed are the corresponding pharmaceutically acceptable, non-toxic esters, ethers and salts.

Prostaglandins are members of a new hormonal system with a remarkable range of biological and pharmaceutical properties. These compounds belong to a group of chemically related 20-carbon chain hydroxy fatty acids containing a five membered ring in the structure and different degrees of unsaturation, a number of which have been reported in. the literature. For a review on prostaglandins and the definition of primary prostaglandins, see for example S. Bergstrom, Recent Progress in Hormone Research, 22, pp. 153-175 (1966) and Science, 157, page 382, (1967) by the same author.

Prostaglandins are widely distributed in mammalian tissues and have been isolated from natural sources in very small amounts. In addition, a number of the naturally occurring prostaglandins have been prepared by chemical synthesis; note for example, J. Am. Chem. $00., 91, page 5,675, (1969); J. Am. Chem. Soc. 92, page 2,586, (1970) and J. Am. Chem. Soc, 93, pages 1,489-l,493, (1971) and references cited therein, W. P. Schneider, et al., J. Am. Chem. Soc., 90, page 5,895, (1968); U. Axen, et al., Chem. Commun., page 303, (1969) and W. P. Schneider, Chem. Commun., page 304, (1969).

Because of the remarkable range of biological and pharmacological properties exhibited by this family of compounds a great deal of interest has focused upon such compounds, and the preparation of analogs of such compounds; accordingly, we have discovered processes and intermediates for preparing modified prostaglandins and derivatives thereof.

The novel prostaglandin derivatives of the present invention can be represented by the following formulas:

? coo" r C":- C CQ/ h R) l :t 'w: 2 n" 3 c0012 G C: u: C R My l 6 R1 HO 1%R (C) i Ho "R wherein each of R and R represents hydrogen,

methyl, ethyl or propyl;

R represents hydrogen, hydroxy or a conventionally hydrolyzable ester or ether thereof;

each of R and R represents hydroxy or a conventionally hydrolyzable ester or ether thereof; R represents methyl, ethyl or propyl, R" represents hydrogen, a lower alkyl group of l to 3 carbon atoms or the pharmaceutically acceptable, nontoxic salts of compounds in which R is hydrogen and n is an integer of from 2 to 9,

provided that when R is a, the hydroxyl group, at-

tached to the same carbon atom as R", is B; and when R is ,8, the hydroxyl group, attached to the same carbon atom as R is a.

The dotted lines shown in the above formulas and in the formulas below indicate that the substituents are in a configuration, i.e., below the plane of the cyclopentane ring.

The wavy lines (l indicate the a or B configuration, or mixtures thereof.

The double bond at C-13 in the compounds of the present invention has the same configuration as in natural prostaglandin of the PGE,, PGE PGF or PGF series, that is, the trans configuration.

The preferred meaning of n is 4, i.e., the preferred compounds of the invention are those having the usual C-2O carbon unit structure of natural prostaglandins.

These novel compounds possess asymmetric centers COOR and thus can be produced as racemic mixtures. The ra- C: C: Q cemic mixtures can be resolved if desired, at appropri- (CH0 )r ;.;3 ate stages by methods known to those skilled in the art, 5 l 6 to obtain the respective individual antimers. It is to be R I R understood that the individual 8R-antimers as well as mixtures of both antimers are encompassed within the scope f h present invention or mixtures in equal proportions of compounds of for- Thus, compounds of formula (A) are mixtuures in 10 mulas: equal proportions of the compounds of the indicated structure and its mirror image represented by the formula:

and

1 -C 12 (A-l) Compounds of formula (B) are mixtures in equal proportions of compounds of formulas:

. (0-4) I 4 x COOR and compounds of formula (D) are mixtures in equal 5 c C proportions of compounds of formulas:

/ 0:: )s -CH 3 com and or mixtures in equal proportions of compounds of for- 3 mulas:

C =0 C COOK or mixtures in equal proportions of compounds of for- 5 U mulas: (Cit -C I1 I R 2 R and and -3 3 1 4 H -CH, COOR 2 n =c Q/ Compounds of formula (C) are mixtures in equal (ID-4) proportions of compounds of formulas.

or mixtures in equal proportions of compounds of formulas:

. \i and & HO

and

(13-6) or mixtures in equal proportions of compounds of formulas:

mirror images for the racemic mixtures and the individ- 35 ual antimers are also encompassed thereby.

The use of the symbol R preceding a substituent designates the absolute stereochemistry of that substituent according to the Cahn-Ingold-Prelog rules [see Cahn, et al., Angew. Chem. Inter. Edit., Vol. 5, p. 385, (1966), errata p. 51l;Cahn, et al., Angew. Chem., Vol. 78, p. 413, (1966); Cahn and Ingold, J. Chem. Soc. (London), 1951, p. 612; Cahn, et al., Experientia, Vol. 12, p. 81, (1956); Cahn. J. Chem. Educ, Vol 41, p. l 16, (1964)]. Because of the interrelation of the designated substituent with the other substituents in the compound having a or B prefixes, the designation of the absolute configuration of one substituent fixes the absolute configuration of all substituents in the compound and thus the absolute configuration of the compound as a whole.

25 lacetate,

The term conventionally hydrolyzable esters or ethers, as used herein, refers to those physiologically acceptable hydrolyzable ester and ether groups employed in the pharmaceutical art which do not significantly adversely affect the pharmaceutical properties of the parent compound. The conventionally hydrolyzable esters are derived from hydrocarbon carboxylic acids. The term hydrocarbon carboxylic acid defines both substituted and unsubstituted hydrocarbon car- 10 boxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation (including aromatic, can be of straight chain, branched chain, or'

cyclic structure, and preferably contain from one to 12 carbon atoms. In addition, they can be substituted by 15 functional groups, for example, hydroxy, alkoxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like, attached to the hydrocarbon backbone chain. Typical conventional hydrolyzable esters thus included within the scope of the term and the instant 20 invention are acetate, propionate, butyrate, valerate,

caproate, enanthate, caprylate, pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate, phenylacetate, diphenylacetate, diethylacetate, trimethylacetate, t-butylacetate, trimethylhexanoate, methylneopentycyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate, hemi-B,B-dimethylglutarate, acetoxyacetate, 2-chloro-4-nitro-benzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, fi-chloropro- O pionate, trichloroacetate, B-chlorobutyrate, bicyclo- [2.2.2]-octanel -carboxylate, 4-methyl-bicyclo- [2.2.2]-oct-2-ene-l-carboxylate, and the like. The preferred conventional hydrolyzable ester is acetate.

Conventional hydrolyzable ethers include the tetrahydrofuran-Z-yl, tetrahydropyrari-Z-yl and 4-methoxytetrahydropyran-4-yl ethers.

The addition salts are derived from pharmaceutically acceptable basic salts, including metal salts such as sodium, potassium, calcium, magnesium, aluminum and the like, as well as organic amine salts such as ammonium, triethylamine, 2-dimethylamino ethanol, 2- diethylamino ethanol, lysine, arginine, caffeine, procaine, N-ethylpiperidine, hydrabamine and the like. The term pharmaceutically acceptable refers to salts which do not significantly adversely affect the properties of the parent compound.

The novel prostaglandin derivatives of the present invention except those which are further substituted at C-l5 by a methyl, ethyl or propyl group can be obtained by a process illustrated by the following sequence of reactions:

(STEP (XIV) wherein R, R and n have the above-indicated mean- 50 R is hydrogen or tetrahydropyranyloxy;

R is hydrogen or hydroxy;

R is methyl, ethyl or propyl;

Ac is a lower acyl group containing from 1 to 4 carbon atoms, particularly acetyl and THP is tetrahydropyranyl.

ln practicing the above illustrated process the starting materials of formula I (racemates or individual antimers) are treated with an excess of the dilithium salt of pent-4-yn-l-ol, in a suitable inert organic solvent to produce the corresponding trihydroxyacetylenic compound of formula ll.

The dilithium salt of pent-4-yn-l-ol reagent is used in amounts comprised between about 5 to about molar equivalents per molar equivalent of starting hemiacetal, using preferably about 10 molar equivalents. This reagent is prepared by reaction of pent-4-yn-l-ol and methyllithium in ether solution, at a temperature of about 7 8 to C., under an inert atmosphere, such as provided by nitrogen or argon, for a period of between 15 to 24 hours, preferably for about 18 hours. The reagent thus prepared is combined with a solution of the hemiacetal of formula I in an ethereal solvent, maintaining the reaction mixture at a temperature comprised between 10 to 30C for about 4 to 10 hours, the reaction time depending upon the temperature used. In the preferred embodiments the reaction is conducted at room temperature (about 25C.) for approximately 6 hours.

Suitable solvents for this reaction are dimethyl ether, diethyl ether, dipropyl ether, dimethoxyethane and the like, particularly diethyl ether.

The product is isolated by dilution with water, extraction with an organic solvent immiscible with water and evaporation of the solvent under reduced pressure, taking care that the temperature does not exceed 20C. The trihydroxylated compound is purified by column chromatography to separate it from the undesired nonpolar by-products. There is obtained a mixture of the 6aand 6B-hydroxy isomers, which can be separated into the individual isomers by thin layer chromatographic techniques, if desired.

The compound of formula II is then esterified under conventional conditions, i.e., using a carboxylic acid chloride or carboxylic acid anhydride in pyridine solution to produce the corresponding triester, the compounds of formula III. The preferred esterifying agent is acetyl chloride, conducting the reaction at room temperature for about 6 hours. In the case of using a carboxylic anhydride, e.g., acetic anhydride, the esterification is slower, requiring reaction times of the order of I2 to 18 hours or higher temperatures to obtain complete esterification.

Upon selective oxidation of the trihydroxyacetylenic compound of formula II with manganese dioxide or 2,- 3-dichloro-5,6-dicyano-l,4-benzoquinone in a suitable inert organic solvent, e.g., chloroform or tetrahydrofuran, there is produced the corresponding dihydroxy-keto-acetylenic compound of formula IV. This reaction is conducted at room temperature for a period of time of about 4 to 6 hours under vigorous stirring, using a large excess of the oxidizing agent. The oxidizing agent is then separated by filtration and the reaction product isolated by conventional techniques, such as evaporation of the solvent and purification of the residue by thin layer chromatography.

The compounds of formula IV are converted into the corresponding o-alkylated derivatives of formula V by reaction with methyl-, ethyL, or propyllithium or the corresponding alkylmagnesium halides. The reaction is effected at a temperature in the range of 10 to 30C., preferably at room temperature using an excess of about 2 to 10 molar equivalents of the alkylating agent per mole of starting material, and preferably about 4 molar equivalents, in a suitable inert organic solvent, using particularly ethereal solvents such as diethyl ether. tetrahydrofuran and the like, for a period of time of about 30 minutes to 2 hours, depending upon the temperature used. The course of the reaction can be followed by t. l .c. The product is isolated from the reaction mixture by conventional means, such as dilution with water, extraction with an organic solvent immiscible with water and evaporation of the solvent under vacuo, at low temperature, followed by purification by thin layer chromatography, obtaining a mixture of the 6oz-hydroxy-6B-alkyland 6B-hydroxy-6a-alkyl compounds of formula V.

The compounds of formula V are then esterified via formation of the lithium salts, followed by reaction with a carboxylic acid chloride in pyridine solution, to produce the corresponding triester of formula VI, in mixture with the diesterified compund of formula VII, which are separated by chromatographic techniques. Thus, the compounds of formula V are allowed to react at room temperature with at least 3 molar equivalents of methyllithium in diethyl ether solution, for a period of time of the order of 1 to 5 hours, preferably for about 3 hours, after which time there is added an excess of the acyl chloride, using particularly acetyl chloride and pyridine, maintaining the reaction mixture at room temperature for several hours to effect esterification, preferably for about 12 to 18 hours. The esterified products are then isolated from the reaction mixture in a conventional manner, preferably by dilution with water, extraction with a solvent immiscible with water, evaporation and separation of the triesterified and diesterified compounds of formulas VI and VII respectively, by chromatography.

The allenic compounds of formula VIII, substituted or unsubstituted at C-4 and unsubstituted at C6 (VIII, R H, Me, Et or Pr and R H) can be obtained by reaction of a triacyloxy acetylenic compound of formula III with a lithium dialkylcopper reagent. The reaction is conducted under an inert atmosphere, i.e., under argon or nitrogen atmosphere in an ether solvent. The dialkylcopper reagents used are those wherein the alkyl moieties are the same, each alkyl group containing from 1 to 3 carbon atoms, e.g., lithium dimethylcopper, lithium diethylcopper, and lithium dipropylcopper, particularly lithium dimethylcopper. These reagents can be prepared by reaction of cuprous iodide with an alkyllithium in diethyl ether as solvent, as described for example by P. Rona et al., in J. Am. Chem. Soc. 9], 3289 (1969).

In this transformation, the reaction conditions and the amount of the lithium dialkylcopper used determine the product obtained. Thus, when the reaction is conducted at very low temperatures, i.e., at temperatures of the order of -50 to 78C for about 3 to 7 hours, using four molar equivalents of the dialkylcopper reagent, employing especially lithium dimethylcopper as reagent, there is obtained the allenic compound unsubstituted at C4 and C6 (VIII, R and R H). The reaction can be followed by t.l.c.; at temperatures of about -C the reaction is complete within about 5 hours. When the reaction is effected at about 0C. for the same reaction time, but using only about one molar equivalent of the organocopper reagent there are obtained the 4-alkyl substituted allenes (VIII, R Me, Et, Pr; R H) in which the alkyl group corresponds to the alkyl group of the reagent.

In any case, the allenic compounds are isolated from the reaction mixture via conventional techniques, such as dilution with ammonium chloride solution, extraction, evaporation of the solvent and purification by chromatography, avoiding temperatures higher than room temperature.

When the above described reactions and a lithium dialkylcopper are effected upon the -alkyl-triesters of formula VI, there are obtained the corresponding 6- alkyl or 4,6-dialkyl allenes of formula VIII (R H, Me, Et, Pr; R Me, Et, Pr), the -monoalkylated compounds being obtained when the reaction is conducted using about 4 molar equivalents of dimethylcopper as reagent, at about 70C, and the dialkyl derivatives when there is used about 1 molar equivalent of the organocopper reagent, at about 0C, as described hereinbefore for the 6-unsubstituted compounds.

The acyloxy groups in any of the allenic compounds represented by formula VIII are then hydrolyzed under alkaline conditions, using a dilute solution of an alkali metal hydroxide or alkali metal carbonate in a lower aliphatic alcohol, at room temperature or below for a period of time sufficient to complete the reaction, ran ging from about 12 to about 24 hours. The preferred reagent used is anhydrous (calcinated) potassium carbonate using methanol as solvent, for a period of time of about 6 to 18 hours, thus obtaining the corresponding dihydroxy compound of formula IX.

Upon oxidation of a dihydroxy compound of formula IX with chromium trioxide, using particularly the stoichiometric amount of an 8N solution of chromic acid in acetone solution in the presence of sulfuric acid (Jones reagent) there is produced the corresponding keto acid derivative of formula X, whose tetrahydropyranyloxy groups are hydrolyzed under mild acidic conditions, to yield the prostatrienoic acid compounds of formula Xl, e.g., racemic or individual antimer 9- keto-l l a,l a-dihydroxyprosta-4,5, l 3-trans-trienoic acid and 9-keto-15a-hydroxyprosta-4,5 ,1 3-transtrienoic acid, the 4 or 6-methyl, ethyl or propyland 4,6-dialkyl derivatives thereof, in which the alkyl groups can be alike or different, as well as the C20 nor or bisnor compounds or the C-20 alkylated derivatives thereof. This hydrolysis is carried out using a weak acid such as acetic acid, oxalic acid, tartaric acid, and the like, in the presence of water. Conveniently, the crude compound of formula X is dissolved in an organic solvent miscible withwater, e.g., tetrahydrofuran, dioxane and the like before addition of the acid reagent. The reaction is conducted at a temperature comprised between 20 to 50C, for a period of time of about 4 to 18 hours, depending upon the temperature used. The preferred reagent is aqueous acetic acid, at concentrations of 40 to 80 percent. It is particularly convenient to use a 65:35 acetic acid-water mixture; however, other concentrations are also practical.

By reaction of the diacyloxy allenic compounds of formula Vlll with 1.1 molar equivalents of anhydrous potassium carbonate in methanol solution, at about 0C., there is selectively saponified the primary acyloxy group. This selective hydrolysis can be followed by t.l.c.; generally, it is complete in about 90 minutes to about 2 hours. The compounds of formula XII thusobtained are oxidized with 8N chromic acid as described hereinabove for the dihydroxylated allenes, to produce the corresponding carboxylic acid, i.e., the

10 derivatives compound of formula Xlll. The protecting groups are in turn hydrolyzed by the above-described methods, i.e., the acyloxy group is hydrolyzed under alkaline conditions, using preferably anhydrous potassium carbonate in methanol, at room temperature or below, to yield the compounds of formula XIV, in which the tetrahydropyranyloxy groups are cleaved by mild acid treatment, using particularly 65 percent aqueous acetic acid, thus obtaining the trihydroxy prostatrienoic acid of formula XV, e.g., 901,1 111,150:- trihydroxyprosta-4,5,lB-trans-trienoic acid and 911,15- a-dihydroxyprosta-4,5,l3-trans-trienoic acid, the 4 or 6-methyl, ethyl or propyl and the 4,6-dialkyl derivatives thereof in which the alkyl group can be the same 15 or different, as well as the C- nor or bisnor compounds or the C-20 alkylated derivatives thereof.

In order to obtain the 9,8-hydroxy isomers of compounds of formula XV, a compound of formula X1 is esterified with ethereal diazomethane, in a conven- 20 tional manner, and the methyl ester thus obtained reand 9,8-hydroxy compounds, which are separated by chromatography on silica gel, obtaining approximately equal amounts of each isomer. The methyl ester group can be hydrolyzed by chemical or enzymatic methods, as described hereinafter in detail.

The novel prostaglandin derivatives of the present invention further substituted at C-1 5 by a methyl, ethyl or propyl group can be obtained by a process illustrated by the following sequence of reactions:

COOH

(XIVA) (XVIII) wherein R, R" R R R and n have the aboveindicated meaning;

R" is hydrogen or methyl;

R is hydrogen or trimethylsilyloxy;

R is hydrogen or trimethylsilyl and TMS is trimethylsilyl (Si[CI-I provided that when R is a, the hydroxyl group, attached to the same carbon atom as R, is B; and when R is ,8, the hydroxyl group, attached to the same carbon atom as R is a.

In practicing the process illustrated above, a compound of formula XIVA (racemic or individual an- (XXIII) (XXVII) timer) in which the hydroxyl group at C-I5 is in a or B-configuration, or mixtures thereof, the B-isomer being prepared by the above described process (I through VIII XII XIV) but starting from the corresponding 3B-tetrahydropyranyloxy isomer of compound of formula I, is converted into an alkyl ester, preferably into the methyl ester, by reaction with diazomethane in ether solution, and thereafter the tetrahydropyranyloxy groups present hydrolyzed with 65 percent aqueous acetic acid, as described hereinabove to yield the corresponding compound of-formula XVI, (R 'Me), in which the hydroxyl group at C9 is in a configuration. The 9,8-hydroxy isomers of compounds of formula XVI are obtained from compounds of formula XI or the ISB-hydroxy isomers thereof, via esterification with diazomethane and reduction of the 9-keto group, as described hereinabove in detail. A compound of formula XVI is then selectively oxidized at C-l with an excess of manganese dioxide or 2,3-dichloro- 5,6-dicyano- 1,4-benzoquinone in a suitable inert organic solvent, e.g., chloroform, tetrahydrofuran, dioxane and the like to produce the corresponding l5-keto compound of formula XVII. When manganese dioxide is used as reagent, this reaction is conducted at room temperature, for a period of time of about 18 to 40 hours, under vigorous stirring, using preferably chloroform or tetrahydrofuran as solvents. The oxidizing agent is added portionwise at 4-6 hours intervals. When the oxidation is effected using 2,3-dichloro-5,6- dicyano-l,4-benzoquinone as reagent, the reaction is preferably conducted at a temperature above room temperature, i.e., at about 40 to 50C. using particularly dioxane as solvent, for a period of time of the order of 14 to 20 hours, preferably for about 18 hours. In any case the course of the reaction can be followed by thin layer chromatography or by periodic determination of the ultraviolet spectrum. When the reaction is complete the oxidizing agent is separated by filtration and the reaction product isolated by conventional techniques such as evaporation of the solvent and purification of the residue by thin layer chromatography or chromatography on Florisil.

Compound XVII is then converted into the corresponding monoor ditrimethylsilyl ether of formula XVIII by procedures known in the art, see for example Pierce, Silylation of Organic Compounds, Pierce Chemical Co., Rockford, Ill. I968 Conveniently, this reaction can be done by using a mixture of hexamethyldisilazane and trimethylchlorosilane or N-trimethylsilyldiethylamine as etherifying agents.

Upon reaction of the trimethylsilyloxy compound with a slight molar excess of an alkyllithium or an alkylmagnesium halide, using particularly methyl-, ethylor propyllithium or methyl-, ethylor propylmagnesium bromides as reagents there are obtained the corresponding 15 l alkyl-152 -hydroxy compounds of formula XIX. In the preferred embodiments, the reaction is carried out using preferably 1.1 to 1.2 molar equivalents of the alkyllithium, or from 6 to 12 molar equivalents of the alkylmagnesium halide per molar equivalent of starting compound, using ether or tetrahydrofuran as solvent, at a temperature comprised between 78C. to room temperature, for a period of time of the order of 2 to l0 hours and under an inert atmosphere, preferably under argon atmosphere. The silyloxy groups of the crude mixture of alkylated compounds are immediately hydrolyzed to afford the compounds of formula XX. This hydrolysis is effected by following known methods for transforming silyl ethers into alcohols, and preferably by dissolving the compound of formula XIX in a lower aliphatic alcohol-water mixture, e.g., 5080 percent aqueous methanol or ethanol, maintaining the solution at a temperature of between 0C, to room temperature for a period of time of about 18 hours to several days, the reaction time depending upon the temperature at which the hydrolysis takes place. This hydrolysis can be optionally done in the presence of a small amount of an organic or inorganic acid, or in the presence of carbon dioxide which will hasten the cleavage of the trimethylsilyloxy groups.

The mixture of ISa-hydroxy-ISB-alkyland 15B- hydroxy-lSa-alkyl compounds of formula XX is separated at this stage by thinlayer chromatographic techniques, and the methyl ester group in the individual isomers is in turn saponified by chemical or enzymatic methods, to yield the corresponding ISa-hydroxy-ISB- alkyl and lSB-hydroxy-lSa-alkyl-prostatrienoic acids of formula XXI.

When this hydrolysis is effected chemically, the alkyl ester compound of formula XX is dissolved in a lower aliphatic alcohol such as methanol or ethanol and treated with an aqueous solution of an alkali metal carbonate, e.g., sodium carbonate or potassium carbonate at a temperature above room temperature, of the order of about 30 to 50C., preferably at about 40C. for a period of time of about 12 to 20 hours, preferably for about 16 hours, thus yielding, after acidification, the corresponding prostatrienoic acid compound of formula XXI. This hydrolysis is preferably conducted under an inert atmosphere, i.e., under nitrogen or argon atmosphere.

Compound XX can be alternatively hydrolyzed by using enzymes in aqueous solutions. For this enzymatic hydrolysis, there is preferably used a crude pancreatic lipase commercially available (Sigma Steapsin), however, other enzyme systems which are known as useful for the hydrolysis of compounds unstable to alkaline or acid conditions can also be practical. Other lipases obtainable from bacterial sources, such as the partially purified lipase obtained from Corynebacterium acnes culture supernatant can also be used, or a lipase of those that are known to act on water insoluble esters of long chain fatty acids (L. Sarda, et a1., Biochem. Biophys. Acta. 23:264 1957) or bakers yeast (C. .l. Sih, et al., J. C. S. Chem. Comm. 240 (1972) The hydrolysis of compound XX with the crude pancreatic lipase can be conducted in a buffered aqueous solution containing sodium chloride and calcium chloride, at a neutral or almost neutral pH, at a temperature of between 22 to 30C., preferably at about 25 to 27C., adjusting the pH of the reaction mixture to 7.2 to 7.4 by addition of, for example dilute sodium hydroxide solution, at intervals. Compound of formula XX is dissolved in the previously prepared buffered lipase aqueous solution by sonication at about 37C. using from about 0.5 ml. to about 1 ml. ofthe lipase solution per milligram of substrate. The methyl ester group is readily hydrolyzed within a short period of time, of the order of 5 minutes to 1 hour. The course of the reaction can be followed by thin layer chroma tography; when the hydrolysis is complete, the free acid can be isolated from the reaction mixture by conventional techniques, such as acidification with a dilute acid solution, e.g., using dilute hydrochloric acid, ex traction with a solvent immiscible with water such as diethyl ether, ethyl acetate, chloroform, methylene chloride, and the like, evaporation of the solvent and purification of the residue by column chromatography, thin layer chromatography or liquid chromatography; good results in the separation of the acid XXI from the lipase have been obtained by column chromatography on Florisil.

By esterification of the carboxylic acid function of compounds of formula X or the 153- tetrahydropyranyloxy epimers (both represented by formula XA), with an ethereal solution of diazomethane followed by hydrolysis of the tetrahydropyranyloxy functions present in the molecule with aqueous acetic acid, as described hereinbefore, and protection of the 9-keto group as the oxime by known methods, i.e., by reaction with hydroxylamine hydrochloride in aqueous methanol and in the presence of sodium acetate, conducting the reaction at room temperature for about 16 to 24 hours, there is obtained the corresponding compound of formula XXII. This compound is then oxidized with manganese dioxide or 2,3-dichloro-5,6- dicyanol ,4-benzoquinone as described hereinabove in detail for the obtention of compound XVII, to produce the corresponding l-keto compound of formula XXIII.

By reaction of a compound of formula XXIII, (R hydroxy) with a silylating agent, using particularly a mixture of hexamethyldisilazane and trimethylchlorosilane or N-trimethylsilyldiethylamine as reagent there is produced the corresponding trimethylsilyloxy derivative represented by formula XXIV.

Treatment of compound XXIII (R H) or compound XXIV with a slight molar excess of an alkyl (methyl-, ethyl-or propyl) lithium or the corresponding alkylmagnesium halide, there is obtained the corresponding ISl-alkyl-lSl-hydroxy compound of formula XXV. This reaction is preferably carried out in ether or tetrahydrofuran solution, using preferably from 1.1 to 1.2 molar equivalents of the alkyllithium or from 6 to 12 molar equivalents of the alkylmagnesium halide per molar equivalent of starting compound. The reaction is effected at a temperature of between 78C. to room temperature, for a period of time of 2 to hours, under an inert atmosphere.

The mixture of lSa-hydroxy-ISB-alkyl and 15B- hydroxy-lSwalkyl compounds is separated into the individual isomers by thin layer chromatography, (previous hydrolysis of the trimethylsilyloxy group when present with aqueous methanol) and thereafter the oxime is hydrolyzed to regenerate the 9-keto function, thus producing the separated 9-keto-l5a-hydroxy-1SB- alkyl and 9-keto-lSB-hydroxy-lSa-alkyl prostatrienoic acid ester compounds of formula XXVI. The deoximation reaction is effected under mild conditions, for example by the methods described by E. J. Corey, et al., in J. Am. Chem. Soc. 92, 5276, (1970) or A. McKillop, et al., J. Am. Chem. Soc. 93, 4918, (1971) and references cited therein.

The first method involves the conversion of the oxime into the O-acetate derivative followed by reaction with an excess, using at least 2 molar equivalents, of chromous acetate in 90 percent aqueous tetrahydrofuran, at a temperature of the order of to 65C. for about 10 to 24 hours.

The second method comprises treatment of the oxime with thallium (III) nitrate, using about I to 1.1 molar equivalents of the reagent per mol of starting compound. The reaction is conducted at room temperature or below for a short period of time, of the order of 5 to minutes, in an inert organic solvent, followed by filtration of the thallium (I) nitrate which precipitates, and brief treatment of the filtrate with dilute acid to decompose the intermediate nitroso compound. In accordance with our invention, this reaction is conducted in methanol solution, at about 20C. using aqueous acetic acid to decompose the nitroso intermediate.

Hydrolysis of the oxime can also be effected using titanium trichloride as described by Timms and Wilsmith, Tetrahedron Letters, 195, (1971).

Alternatively the compounds of formula XXVI (wherein R is hydrogen) are obtained by oxidation of the compounds of formula XX (wherein R" is hydrogen) with chromium trioxidedipyridine complex [prepared as described by J. C. Collins et al., Tetrahedron Letters, 3363 (1968)] Alternatively, the compounds of formula XXVI (wherein R is hydrooxyl) are obtained by treating the compounds of formula XX (wherein R" is hydroxyl) according to the method disclosed by E. W. Yankee, et al., J. A. C. S., 94, 3651, (1972); namely, selective silylation at the ll-position of XX (wherein R is hydroxyl), followed by oxidation with Collins reagent and subsequent hydrolysis with aqueous methanol containing a trace of acetic acid to yield the compounds of formula XXVI (wherein R" is hydroxyl).

Alternatively, the hydrolysis of the oxime can be effected on the mixture of the 15a and ISB-hydroxy isomers, separating the individual isomers afterwards by thin layer chromatography.

The alkyl ester group in compounds of formula XXVI is hydrolyzed by chemical or enzymatic meth-. ods, e.g., by reaction with potassium carbonate in aqueous methanol or with a crude pancreatic lipase, respectively, as described hereinbefore in detail for the hydroxylated compounds, thus producing the free acids of formula XXVII.

The hydroxyl groups in compounds of formulas XI and XV and the secondary hydroxyl groups in compounds of formulas XXI and XXVII can be esterified or etherified in a conventional manner, to produce mono-, di-, or triesters, or mono-, dior triethers, depending upon the particular prostaglandin derivatives. Esterification can be accomplished by reaction of the hydroxylated compound with a carboxylic acid anhy dride or chloride of less than 12 carbon atoms in pyridine solution.

Etherification can also be carried out by conventional techniques. For example, reaction with dihydropyran, dihydrofuran or 4-methoxy-5,6-dihydro-2H- pyran in an inert solvent such as, for example, methylene chloride or benzene and in the presence of an acid catalyst (e.g., p-toluenesulfonic acid, p-toluenesulfonyl chloride) produces the tetrahydropyran-Z-yloxy, tetrahydrofuran-2-yloxy or 4'-methoxytetrahydropyran-4'-yloxy derivatives, respectively.

Although the esterification or etherification reactions are usually effected using an excess of the esterifying or etherifying agents, it is preferable to use at least one molar equivalent of said reagents per hydroxyl group present in the starting compound.

The alkyl esters of the carboxylic acid function can be prepared by treatment of the free acid with an excess of a diazoalkane such as diazomethane, diazoethane or diazopropane in ether or methylene chloride solution, in a conventional manner, or by reaction with the desired lower alkyl iodide in the presence of lithium carbonate, at room temperature.

The salt derivatives of the prostanoic acids of the present invention can be prepared by treating the corresponding free acids with about one molar equivalent of a pharmaceutically acceptable base per molar equivalent of free acid. Suitable pharmaceutically acceptable bases include, for example, sodium hydroxide, trimethylamine, triethylamine, tripropylamine, ,B-(dimethylamino) ethanol, B-(diethylamino) ethanol, arginine, lysine, caffeine, procaine and the like. Typically, the reaction is conducted in an aqueous solution, alone or in combination with an inert water miscible organic solvent, at a temperature of about from 0 to 30C preferably at room temperature. Typical inert, water misci-' treated with at least one half molar equivalent of the pharmaceutically acceptable base.

When the above-described processes are effected using racemic mixtures as starting materials, each and every intermediate and final product will be a racemate, while when starting with an R-antimer, each and every intermediate and final product will be an R- antimer.

The compounds of formula I used as starting materials in the above described processes can be obtained by the following sequence of reactions:

wherein R represents methyl or benzyl;

R represents hydrogen or p-phenylbenzoyl; R

represents p-phenylbenzoyl,

M represents sodium or thallium, and

n is as defined above.

In the above reaction scheme, compounds of formulas (8) through (IA) and (7A) through(lB) can be in the form of racemates or as the corresponding individual antimers, in particular the R-antimers. The lR- antimers of 7A, (R benzyl) and (8) have been described by E. J. Corey et al, in J. Am. Chem. Soc. 93, 1491 (1971), while the l'R-antimer of 7A, (R methyl) has been described by E. J. Corey, et al., in J. Am. Chem. Soc. 92, 397 (1970).

Briefly, the method for the obtention of the starting materials comprises the reaction of cyclopentadienyl sodium or cyclopentadienyl thallium (1), obtained by reaction of cyclopentadiene with sodium hydride or aqueous thallous sulfate in the presence of potassium hydroxide (E. J. Corey, et al., J. Am. Chem. Soc. 93, 1489, (1971 with a slight excess of chloromethyl methyl ether or chloromethyl benzyl ether in tetrahydrofuran at approximately 55C., to yield respectively the methoxymethyl-1,3-cyclopentadiene 2 (R methyl) or 5-benzyloxymethyl-l,3-cyclopentadiene 2 (R benzyl) which are subjected to the Diels Alder reaction with an excess (about 5 molar equivalents) of 2- chloroacrylonitrile in the presence of cupric fluoroborate as catalyst to yield a mixture of the endo-exo cyano nitriles of formulas (3) and (4) (R methyl or benzyl, respectively). This mixture of stereoisomeric nitriles is treated with potassium hydroxide in dimethyl sulfoxide to yield the anti-bicyclic ketones of formula (5), i.e.,

-" coca cn ort LL) 7 7-syn-methoxymethyl-2-norbornen-5-one (R methyl) or 7-syn-benzyloxymethyl-2-norbornen-5-one (R benzyl) respectively, which upon reaction with a slight molar excess of m-chloroperbenzoic acid in methylene chloride in the presence of sodium bicarbonate results in selective Baeyer-Villiger oxidation to form the corresponding lactone (6), namely 2-oxa-3- ox0-A -8-syn-methoxy-methylbicyclo (3.2.1) octane (R methyl) and 2-oxa-3-oxo-A -8-syn-benzyloxymethylbicyclo (3.2.1) octane (R benzyl). Saponification of the foregoing lactones of formula (6) with 2.5 equivalents of sodium hydroxide in aqueous methanol, followed by neutralization with carbon dioxide and treatment with 2.5 equivalents of aqueous potassium triiodide solution at 05C. produce the respective hydroxy-iodolactones of formula (7), namely (2'a,4'adihydroxy-3 'B-iodo-S 'B-methoxymethylcyclopentla-yl) -acetic acid l,2'-lactone (R methyl, R H) and (2 'a,4a-dihydroxy-3 'B-iodo-S B- benzyloxymethylcyclopent-l'a-yl)-acetic acid l,2'- lactone (R benzyl, R H) which are esterified with p-biphenylcarboxylic acid chloride in pyridine, under conventional conditions to yield the corresponding pphenylbenzoates (7, R p-phenylbenzoyl).

These compounds are then submitted to deiodination using tri-n-butyl tin hydride in the presence of catalytic amounts of azobisisobutyronitrile in benzene solution, and thence to cleavage of the S'B-benzyloxymethyl or SB-methoxymethyl group to produce the hydroxymethyl compound (8).

The benzyloxymethyl group is cleaved by hydrogenolysis in the presence of palladium-charcoal and perchloric acid as catalysts, in a suitable organic solvent; the methoxymethyl group is hydrolyzed by reaction hydroxymethylcyclopentl 'a-yl)-acetic acid 1,2-

lactone is obtained as described by E. J. Corey et al in J. Am. Chem. Soc. 93, 1491, (1971) via base catalized hydrolysis of the lactone (6) (R benzyl) to the corresponding hydroxyacid, resolution of the hydroxyacid as the (+)-amphetamine salt followed by iodolactonization of the resolved lR-antimer, esterification with p-phenylbenzoylchloride, deiodination with tri-nbutyltin hydride and hydrolysis of the benzyloxymethyl group.

Oxidation of a racemic hydroxymethyl compound (8) or the lR-antimer with chromium trioxidedipyridine complex (prepared as described by J. C. Collins, et al., in Tetrahedron Letters 3363, (1968) in methylene chloride, at about C. affords the aldehyde (9), (racemic mixture or R-antimer) which without purification is transformed stereospecifically into the corresponding trans-enone lactone of formula (10). This transformation involves a modified Wittig reaction, which comprises treatment of the aldehyde of formula (9) with the sodium anion of a dimethyl-2-oxo-nalkylphosphonate of the formula:

wherein m is an integer of from 2 to 9, in dimethoxy ethane solution. The reagents used are: dimethyl 2-oxopentylphosphonate, dimethyl 2-oxohexylphosphonate, dimethyl 2-oxoheptylphosphonate, dimethyl 2-oxo-octylphosphonate, dimethyl 2- oxononylphosphonate, dimethyl 2- oxodecylphosphonate, dimethyl 2-oxoundecylphosphonate and dimethyl 2-oxododecylphosphonate.

These reagents are conveniently prepared in accordance with the method described by E. J. Corey, et al., in J. Am. Chem. Soc. 88, 5654, (1966) from dimethyl a-lithiomethanephosphonate and a methyl or ethyl ester of a n-alkanoic acid containing from 4 to 10 carbon atoms, e.g., ethyl n-butanoate, methyl nhexanoate, and ethyl n-decanoate. The reaction is conducted at temperatures of the order of 0 to 40C, preferably at room temperature or below for about 1 to 4 hours, under an inert atmosphere, using at least one molar equivalent of the reagent per mole of aldehyde, and preferably 1.2 to 2 moles.

Treatment of the racemic enone (10) or the l'R- antimer with an excess of zinc borohydride in dimethoxyethane, at room temperature for about 1 hour produces a mixture of the corresponding a and B-hydroxy compounds, which is separated by thin layer chromatography on silica gel to obtain the desired a-hydroxylated compound in pure form (1 1, R pphenylbenzoyl). The p-phenylbenzoyloxy group is then hydrolyzed under alkaline conditions, using preferably anhydrous potassium carbonate in methanol, and the diol is etherified with dihydropyran in methylene chloride solution and in the presence of p-toluenesulfonic acid, to give the bistetrahydropyranyloxy compound (12), (racemic mixture or lR-antimer) which by reduction with diisobutylaluminum hydride in toluene, at about C produces the lactol of formula (1A), e.g., [2 'a-hydroxy-4'oz-tetrahydropyranyloxy-5 B-( 3 'atetrahydropyranyloxyoct-l "(t)-en-l "-yl)-cyclopentl'a-yl]-acetaldehyde-l,2"hemiacetal, (1A, n 4), [2- 'a-hydroxy-4'a-tetrahydropyranyloxy-S /3-( 3 'atetrahydropyranyloxyhex-1"(t)-en-1"-yl)-cyclopentla-yl]-acetaldehyde l,2'-hemiacetal, (1A, n 2) and [2'a-hydroxy-4'a-tetrahydropyranyloxy-5 ,B-( 3 atetrahydropyranyloxytridec-1"(t)-en-l"-yl)- cyclopent-l a-yl]-acetaldehyde l,2'-hemiacetal, (1A, n 9) or the l'R-antimers thereof.

By reaction of a racemic hydroxy iodolactone of formula (7A) or the l'R-antimers thereof with freshly distilled phosphorous oxychloride in pyridine solution, first at 0C and thereafter at room temperature there is obtained the corresponding dehydrolactone compound (racemic or l'R-antimer) of formula (13).

The l'R-antimers of (7A), namely l'R-(2oz,4adihydroxy-3 'B-iodo-S 'B-benzyloxymethylcyclopentla-yl) acetic acid l,2'-lactone (7A, R benzyl) and 1'R-( 2'oz,4'a-dihydroxy-3 'B-iodo-S 'B- methoxymethylcyclopent-la-yl)-acetic acid l,2'- lactone (7A, R methyl) are obtained as described by E. J. Corey, et al., in J. Am. Chem. Soc. 93, 1491 (1971) and in J. Am. Chem. Soc. 92, 397, (1970) respectively, via base catalyzed hydrolysis of the corresponding lactone (6) to the hydroxyacid, resolution of the hydroxyacid as the (+)-amphetamine salt for the benzyloxymethyl compound or as the ()-ephedrine salt for the methoxymethyl compound and iodolactonization of the respective l'R-antimeric acid). In order to prevent hydrogenolysis of the allylic hydroxy] during the reduction of the double bond, the lactone group in a compound of formula (13) is opened by treatment with 2N methanolic sodium hydroxide followed by careful neutralization with 3N hydrochloric acid in ethyl acetate to pH 6, to produce the hydroxyacid (14) (racemic mixture or lR-antimer). Catalytic reduction of this hydroxyacid with Raney nickel in methanol solution followed by brief exposure to acid produces the corresponding lactone l5 which is hydrolyzed to the corresponding hydroxymethyl compound (16) (racemic or l'R-antimer) by the above-mentioned methods, i.e., by hydrogenolysis in the case of the benzyloxymethyl compound (15, R benzyl) or by reaction with boron tribromide for the methoxymethyl derivative (15, R methyl).

A hydroxymethyl compound of formula (16) is then converted into the desired lactol of formula (18) by oxidation with chromium trioxide-dipyridine complex to the aldehyde, condensation of the aldehyde with the sodium anion of a dimethyl 2-oxo-n-alkylphosphonate of the type previously mentioned to produce the corresponding trans-enone lactone, selective reduction of the keto group with zinc borohydride to yield a mixture of the a and B-hydroxy isomers, separation of the isomers by thin layer chromatography, etherification of the 3"a-hydroxy compound with dihydropyran and reduction of the lactone ring with diisobutylaluminum hydride, as described in detail hereinbefore with regard to the transformation of a compound (8) into a compound (1A).

The compounds, esters and salts of the invention exhibit prostaglandin-like biological activities and thus are useful in the treatment of mammals where the use of prostaglandins are indicated. The compounds, esters and salts of the invention are bronchodilators and thus are useful in treating mammals for bronchial spasm or wherever strong bronchodilators are indicated. These compounds are also useful in controlling or palliating hypertension in mammals and further exhibit central nervous system depressant activity in mammals, and are useful as sedatives. In addition, the compounds are useful for inducing labor, in pregnancy, and for inducing menses to correct or reduce menstrual abnormalities.

The compounds and/or salts, of the invention, can be administered in a wide varietyof dosage forms, either alone or in combination with other pharmaceutically compatible medicaments, in the form of pharmaceutical compositions suited for oral or parenteral administration or inhalation in the case of bronchodilators. The compounds are typically administered as pharmaceutical compositions consisting essentially of the compounds and/or salts, of the invention, and a pharmaceutical carrier. The pharmaceutical carrier can be either a solid material, liquid or aerosol, in which the compound and/or salt is dissolved, dispersed or suspended, and can optionally contain small amounts of preservatives and/or pH-buffering agents. Suitable preservatives which can be used include, for example, benzyl alcohol and the like. Suitable buffering agents include, for example, sodium acetate and pharmaceutical phosphate salts and the like.

The liquid compositions can, for example, be in the form of solution, emulsions, suspensions, syrups, or elixirs. The solid compositions can take the form of tablets, powders, capsules, pills or the like, preferably in unit dosage forms for simple administration or precise dosages. Suitable solid carriers include, for example, pharmaceutical grades of starch, lactose, sodium saccharin, talcum, sodium bisulfite and the like.

For inhalation administration, the compounds and/or salts can, for example, be administered as an aerosol comprising the compounds or salts in an inert propellant together with a cosolvent (e.g., ethanol) together with optional preservatives and buffering agents. Additional general information concerning the inhalation administration of aerosols can be had by reference to Us. Pat. Nos. 2,868,691 and 3,095,355.

the compounds of this invention are typically administered in dosages of about from 0.01 to mg. per Kg. of body weight. The precise effective dosage will, of course, vary depending upon the mode of administration, condition being treated and host.

The following Preparations and Examples illustrate the invention, but are not intended to limit its scope. The starting materials and products obtained in Preparation 8, part C through 18 and Examples 1 to 40 are racemates, while the starting materials and products obtained in Preparations 8' through 18 and Examples 1A through 40A are the corresponding individual antimers. The abbreviation t.l.c. refers to thin-layer chromatography and all mixture ratios used with regard to liquids refer to volume ratios. Also, where necessary, preparations and examples are repeated to provide sufficient starting material for subsequent examples.

PREPARATION 1 A. To a stirred solution of 125 g. of thallium sulfate and 50 g. of potassium hydroxide in 750 ml. of water are added, under an atmosphere of argon, 43 ml. of

freshly distilled cyclopentadiene and the mixture is vigorously stirred for 10 minutes; the yellow precipitate formed is filtered off, washed with ice water, methanol and ether, to yield 132 g. of cyclopentadienylthallium.

B. A mixture of2l6.28 g. of benzyl alcohol, 61.44 g. of paraformaldehyde, 481.6 g. of anhydrous magnesium sulfate and 1,200 ml. of methylene chloride is cooled to a temperature of between 50 to 55C. in a dry ice-acetonitrile bath, and the stirred cold solution is saturated with anhydrous hydrogen chloride gas. The reaction mixture is kept at 50 to 55C. for 10 minutes further, and then the excess of hydrogen chloride is eliminated by passing a stream of nitrogen during 30 minutes. The reaction mixture is filtered and the solid material washed well with pentane, and the combined filtrates are evaporated to dryness at a temperature below 30C., to produce an oil which is distilled under reduced pressure to yield chloromethyl benzyl ether.

C. A suspension of 132 g. of cyclopentadienylthallium in 200 ml. of anhydrous ether is cooled to *20C. in a dry ice-carbon tetrachloride bath. To the cooled mixture are added under stirring and under an argon atmosphere, in a 15-minute period, g. of chloromethyl benzyl ether. The reaction mixture is stirred for 3 /2 hours at 20C., it is then filtered in a filtration flask previously cooled to 78C. and the solid precipitate washed with cold pentane (78C).

The filtered solution is immediately added to a mixture of 216 g. of anhydrous a-chloroacrylonitrile and 30 g. of anhydrous cupric fluoroborate, previously cooled to 78C. The reaction mixture is evaporated to half its original volume at a temperature not higher than 0C., and the concentrate is stirred at 0c. for 48 hours. The reaction mixture is then poured into 200 ml. of saturated sodium chloride solution, and extracted three times with ether. The combined extracts are washed with saturated sodium bicarbonate solution (2 X 200 ml.) and saturated sodium chloride solution (2 X 200 ml.), dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue is purified by filtration through g. of silica gel using benzene as eluant, thus obtaining the pure 2- chloro-2-cyano-A -7syn-benzyloxymethylbicyclo- (2.2.1 )-heptane [mixture of (3) and (4), R benzyl].

PREPARATION 2 To a well-stirred slurry of 74.1 g. of cyclopentadienylthallium in 100 ml. of anhydrous ether cooled to 20 to 22C. (internal temperature) in a dry icecarbon tetrachloride bath under an argon atmosphere, are added dropwise, in a l5-minute period, 20.13 g. of chloromethyl methyl ether and the slurry is stirred at -20 to 22C. for 7 hours. The reaction mixture is then filtered into a precooled (70C, dry iceacetone) flask and the residue of thallium chloride washed with three 100 ml. portions of cold (70C) ether. The combined filtrate is added-dropwise from a dropping funnel with a dry ice jacket to a suspension of 29.65 g. of cupric tetrafluoroborate in 87.5 g. of anhydrous a-chloroacrylonitrile maintained at 0C. When the addition is complete, the mixture is stirred at 0C. in the dark for 18 hours. One hundred milliliters of saturated sodium chloride solution are then added and the reaction mixture extracted with ether. The ether extracts are successively washed with saturated sodium bocarbonate (2 X 100 ml.) and sodium chloride (2 X 100 ml.), and dried over magnesium sulfate. Evapora- PREPARATION 3 To a stirred solution of 100 g. of 2-chloro-2-cyano- A -7-syn-benzyloxymethylbicyclo-(2.2. 1 )-heptane in 368 ml. of dimethylsulfoxide is added dropwise, in a -minute period and under argon atmosphere, a hot solution of 105.2 g. of potassium hydroxide in 52.6 ml. of water. The reaction mixture is stirred for 28 hours at room temperature, diluted to twice its volume with ice water and extracted several times with ether. The combined organic extract is washed twice with saturated sodium carbonate solution, dried over magnesium sulfate and evaporated to dryness. The residue is purified by distillation under high vacuum (0.6 mm.) to yield 7-syn-benzyloxymethyl-Z-norbornen-S-one, (5, R benzyl), homogeneous on t.l.c.

By the same procedure but using 2-chloro-2-cyano- A -7-syn-methoxymethylbicyclo-( 2.2.1 )-heptane in lieu of 2-chloro-2-cyano-A -7-synbenzyloxymethylbicyclo-(2.2.l )-heptane there is obtained 7-syn-methoxymethyl-2-norbornen-5-one (5, R methyl).

PREPARATION 4 To a suspension of 55 g. of m-chloroperbenzoic acid and 43.5 g. of sodium bicarbonate in 570 ml. of anhydrous methylene chloride are added 57 g. of 7-synbenzyloxymethyl-Z-norbornen-S-one, in a 15 minute period and under stirring, maintaining the temperature at about 25C. the reaction mixture is stirred for 3 hours further and diluted with methylene chloride. The resulting mixture is vigorously stirred with 470 ml. of saturated aqueous sodium sulfite solution, the organic layer is separated and washed with saturated sodium sulfite solution. The aqueous phase is extracted with methylene chloride and the combined organic methylene chloride extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, thus yielding 2-oxa-3-oxo-A -S-syn-behzyloxymethylbicycle-(3.2.1 )-octane as an homogeneous oil, (6, R benzyl).

By the same procedure but using 7-synmethoxymethyl-2-norbornen-5-one in place of 7-synbenzyloxymethyl-Z-norbornen-S-one there is obtained 2-oxa-3-oxo-A -8-syn-methoxymethylbicyclo-( 3.2.1 octane, (6, R methyl).

PREPARATION 5 To a solution of 60 g. of 2-oxa-3-oxo-A -8-synbenzyloxymethylbicyclo-(3.2.l)-octane in 70 m1. of methanol is added, at 0C., a solution of 30 g. of sodium hydroxide in 247 ml. of water, and the resulting mixture is stirred at room temperature for 3 hours. The methanol is then evaporated under vacuo at a temperature below 30C., cooled to 0C. and extracted with ether to eliminate the unsaponifiable products. The aqueous phase is neutralized with carbon dioxide and immediately treated with a solution of 188.1 g. of iodine and 369 g. of potassium iodide in 275 ml. of water. The reaction mixture is stirred for 48 hours at 0C. and diluted with sodium sulfite solution until complete decoloration. It is then saturated with sodium potassium tartrate and extracted with methylene chloride.

The organic extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue is crystallized from ether-methylene chloride, to yield the pure (2'a,4'a-dihydroxy-3'B-iodo- 5 'B-benzyloxymethylcyclopent-l a-yl)-acetic acid 1,2'-lactone, (7, R benzyl, R H).

Similarly, starting from 2-oxa-3-oxo-A -8-synmethoxymethylbicyclo-( 3.2. l octane there is obtained (2'a,4'a-dihydroxy-3 'B-iodo-S 'B- methoxymethylcyclopent-l 'a-yl)-acetic acid 1,2- lactone (7, R methyl, R H).

. PREPARATION 6 iodo-5 'B-benzyloxymethylcyclopent-l a-yl)-acetic acid 1,2-lactone in 152 ml. of anhydrous pyridine is added 32.8 g. of p-biphenylcarboxylic acid chloride. The resulting solution is stirred at room temperature for 1 hour; 9 ml. of water are then added, and the mixture stirred for 1 hour to destroy the excess reagent. The solvents are eliminated under reduced pressure and the residue is dissolved in methylene chloridecyclohexane (3:2the organic solution is washed successively with 10 percent hydrochloric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated, to yield (20z-hydroxy-4a-pphenylbenzoyloxy-3 'B-iodo- 5 ',Bbenzyloxymethylcyclopent-l 'a-yl)-acetic acid l,2'- lactone, (7, R benzyl; R p-phenylbenzoyl) which can be purified by crystallization.

By the same procedure, (2a,4'a-dihydroxy-3B- iodo-S ,B-methoxymethylcyclopent-l a-yl)-acetic acid l,2-lactone is converted into (2oz-hydroxy-4'a-pphenylbenzoyloxy-3 'B-iodo-S B- methoxymethylcyclopent-l'a-yl)-acetic acid l,2'- lactone (7, R methyl, R p-phenylbenzoyl).

PREPARATION 7 To a solution of 61 g. of (2'a-hydroxy-4'a-pphenylbenzoyloxy-3 ,B-iodo-5 'B- benzyloxymethylcyclopent-l 'oz-yl)-acetic acid l,2'- lactone in 610 ml. of benzene (dried over molecular sieves) is added 45.25 g. of tri-n-butyl tin hydride, prepared according to the procedure of H. G. Kuivila and O. F. Beumel, Jr., J. Am. Chem. Soc., 83, 1246, (1961) and 211 mg. of azobisisobutyronitrile. The mixture is stirred at 50C. for 30 minutes. Then the benzene is removed by evaporation under reduced pressure, the oily residue is dissolved in 1.5 l. of ether and the ethereal solution is washed several times with 5 percent aqueous sodium hydroxide solution and then with saturated sodium chloride solution, dried over magnesium sulfate.

(2 'a-hydroxy-4a-p- PREPARATION 8 A. To a prehydrogenated suspension of 1 g. of 10 percent palladium charcoal catalyst in 200 ml. of anhydrous dimethoxyethane are added 10 g. of (2'0:- hydroxy-4 'a-p-phenylbenzoyloxy5 'B- benzyloxymethylcyclopent-1'a-yl)-acetic acid 1,2- lactone and 1 ml. of perchloric acid, and the mixture is stirred under hydrogen atmosphere until the absorption of hydrogen ceases. The catalyst is then separated by filtration and washed with ether. The combined organic filtrates are washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from chloroform yields (2'oz-hydroxy-4'a-pphenylbenzoyloxy-SB-hydroxymethylcyclopent-1'ayl)-acetic acid l,2'-lactone (8).

B. A stirred solution of 15 g. of (2'rx-hydroxy-4'a-pphenylbenzoyloxy-S 'B-methoxymethylcyclopent-1 'ayl)-acetic acid 1,2'-lactone in 190 m1. of anhydrous methylene chloride is cooled to 78C. in a dry iceacetone bath and treated with 25 ml. of boron tribromide. The stirred mixture is allowed to warm rapidly to C. and kept at this temperature for 50 minutes. To the resultant solution is then added 270 ml. of ether to decompose excess boron tribromide, maintaining the reaction mixture at 0C. It is then poured into a vigorously stirred slurry of 95 g. of sodium bicarbonate in 500 ml. of a saturated solution of sodium potassium tartrate; the organic layer is separated and the aqueous phase extracted with methylene chloride. The combined organic extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is purified by crystallization from chloroform to afford (2or-hydroxy-4'a-p-phenylbenzoyloxy- B-hydroxymethylcyclopent-1 'a-y1)-acetic acid 1.2- lactone, identical to the product obtained in Part A.

C. To a suspension of 300 g. of Celite, diatomaceous earth (dried for 24 hours at 105C) and 61.5 g. of chromium trioxide-dipyridine complex [prepared as described by J. C. Collins, et al., Tetrahedron Letters 3363, (1968)] in 610 ml. of anhydrous methylene chloride, cooled to -5C. are added under stirring 10 g. of (2 'a-hydroxy-4'a-p-phenylbenzoyloxy-S ,8- hydroxymethylcyclopent-l'ayl)-acetic acid 1,2- lactone dissolved in 60 ml. of methylene chloride and the mixture is stirred for 10 minutes further, maintaining the temperature between 5 and 0C.; 100 g. of sodium bisulfite monohydrate are then added and the mixture is stirred for an additional 10-minute period, filtered through magnesium sulfate and the solids washed with methylene chloride, receiving the filtrate in a flask cooled to -60C. in a dry ice-acetone bath. The combined filtrates are evaporated to dryness under reduced pressure, at a temperature below 0C, obtaining (2 'a-hydroxy-4 cv-p-phenylbenzoyloxy-S '13- formylcyclopent-l a-yl)-acetic acid 1,2-lactone (9)as an homogeneous oil.

PREPARATION 8 By following the oxidation method of part C of Preparation 8, starting from the l'R-antimer of (8), namely 1R-( 2oz-hydroxy-4'a-p-phenylbenzoyloxy-S 'B- hydroxymethylcyclopent-l a-yl)-acetic acid 1,2- lactone [obtained as described by E. J. Corey, et al., in J. Am. Chem. Soc. 93, 1491, (1971) there is obtained lR-( 2'a-hydroxy-4 'a-p-phenylbenzoyloxy-S 'B- formylcyclopent-la-yl)-acetic acid 1,2'-lactone (l'R- antimer of 9).

PREPARATION 9 A solution of 22 g. of (2'a,4a-dihydroxy-3'B-iodo- 5 [3-benzyloxymethylcyclopent-1 'a-yl )-acetic acid l,2'-lactone in 60 ml. of anhydrous pyridine is cooled to 0C. and treated dropwise, under stirring, with a mixture of 8 ml. of phosphorous oxychloride and 20 ml. of pyridine. When the addition is complete, the reaction is stirred for 30 minutes at room temperature, and the solvent is eliminated under reduced pressure. The oily residue is dissolved in methylene chloride, and the organic solution washed with 10 percent hydrochloric acid solution, reextracting the aqueous phases with methylene chloride.

The combined organic extracts are then washed with saturated sodium sulfite solution until complete decoloration, dried over magnesium sulfate and evaporated to dryness under reduced pressure to yield (2'0:- hydroxy-S B-benzyloxymethylcyclopent-3 -en- 1 'a-yl acetic acid 1,2-lactone 13, R benzyl) as a colorless oil.

In a similar manner, starting from (2'a,4adihydroxy-3 'B-iodo-S 'B-methoxymethylcyclopent-l 'ayl)-acetic acid l,2-lactone there is obtained (2'01- hydroxy-S B-methoxymethylcyclopent-3 -en-1'a-yl)- acetic acid l,2'-lactone (13, R methyl).

PREPARATION 9 Substituting 1 'R-( 2'a,4a-dihydroxy-3 B-iodo-S 'B- benzyloxymethylcyclopent-1 'a-yl)-acetic acid 1,2- lactone obtained as described by E. J. Corey, et al., in J. Am. Chem. Soc. 93, 1491, (1971), for (2'a,4'a dihydroxy-3 ,B-iodo-S 'B-benzyloxymethylcyclopent- 1'a-yl)-acetic acid 1,2'-lactone in the procedure of Preparation 9 is productive of I'R-(Z'a-hydroxy-S'B- benzyloxymethylcyclopent-3 '-en-1 'oz-yl )-acetic acid 1,2'-lactone, (l'R-antimer of 13, R benzyl).

Likewise the substitution of l'R-(2'a,4'a-dihydroxy- 3 'B-iodo-S 'B-methoxymethylcyclopent-l 'a-yl)-acetic acid l,2'-lactone (obtained as described by E. J. Corey, et al., in J. Am. Chem. Soc. 92, 397, 1970), in Preparation 9 is productive of I'R-(Z'a-hydroxy-S'B- methoxymethylcyclopent-3 '-en-l 'a-yl)-acetic acid 1,2'-lactone (l'R-antimer of 13, R methyl).

PREPARATION 10 A stirred solution of 13 g. of (Z'a-hydroxy-S'B- benzyloxymethylcyclopent-3 '-en-l a-yl)-acetic acid 1,2'-lactone in 20 m1. of methanol is cooled to 0C. and treated dropwise with a solution of 6.5 g. of sodium hydroxide in 65 ml. of water; when the addition is complete the reaction mixture is stirred for I hour at room temperature. The methanol is then eliminated under reduced pressure at a temperature below 30C., and the resulting aqueous solution cooled to 0C and extracted with ether, to eliminate the unsaponifiable products. The aqueous phase is carefully acidified to pH 5-6 with 3N hydrochloric acid at 0C., ml. of ethyl acetate are then added and thereafter the reaction is acidified to pH 23. The organic phase is separated and the aqueous phase is saturated with sodium chloride, extracting it with six 50 ml. portions of ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under vacuo. Crystallization of the residue from hexane-methylene chloride gives the pure (2 'a-hydroxy-S 'B- benzyloxymethylcyclopent-3en-loz-yl)-acetic acid (14, R benzyl).

In a similar manner (2'a-hydroxy-5 B- methoxymethylcyclopent-3 -en-l 'a-yl )-acetic acid l,2'-lactone is converted into (2'a-hydroxy-5B- methoxymethylcyclopent-3-en-l 'a-yl)-acetic acid (14, R methyl).

PREPARATION 10 In accordance with the method of Preparation 10, l- 'R-(Z'a-hydroxy-S'B-benzyloxymethylcyclopent-3'-enla-yl)-acetic acid l,2-lactone and IR-(Za-hydroxy- 5'B-methoxymethylcyclopent-3 '-en-l 'oz-yl)-acetic acid l,2'-lactone are converted respectively into lR-(2ahydroxy-S 'B-benzyloxymethylcyclopent-3 '-en-l 'a-yl acetic acid (l'R-antimer of 14, R benzyl) and l'R- (Z'a-hydroxy-S'B-methoxymethylcyclopent-3 -en-1'ozyl)-acetic acid (1R-antimer of 14, R methyl).

PREPARATION II To a prehydrogenated suspension of 10 g. of Raney nickel in 200 ml. of methanol is added 13 g. of (2's!- hydroxy-S 'B-benzyloxymethylcyclopent-3 '-en-l 'a-yl acetic acid, and the mixture is stirred under hydrogen atmosphere until the uptake of hydrogen ceases; the catalyst is then separated by filtration and washed well with ether. The combined organic filtrates are evaporated to dryness under reduced pressure and the oily residue is dissolved in 200 ml. of ethylacetate. The resultant solution is then treated with 3N hydrochloric acid until a pH of 2-3 is obtained, stirring the reaction mixture for 30 additional minutes. It is then neutralized with sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness under vacuo, thus yielding (2'a-hydroxy-S'B-benzyloxymethylcyclopent-l 'a-yl)- acetic acid l,2-lactone, (15, R benzyl) homogeneous on t.l.c.

In a similar manner, (Z'a-hydroxy-SB- methoxymethylcyclopent-4-en-l'a-yl)-acetic acid is converted into (2 "oz-hydroxy-S B- methoxymethylcyclopent-l a-yl)-acetic acid l,2- lactone (15, R methyl).

PREPARATION 11' In accordance with the method of Preparation 1 1, l- R-(Z'a-hydroxy-S'B-benzyloxymethylcyclopent-3'-enla-yl)-acetic acid and I'R-(Za-hydroxy-SB- methoxymethylcyclopent-3'-en-l a-yl)-acetic acid are converted respectively into I'R-(Za-hydroxy-SB- benzyloxymethylcyclopent-l'a-yl)-acetic acid l,2- lactone l 'R-antimer of 15, R= benzyl) and 1R-(2ahydroxy-5 'B-methoxymethylcyclopent-1 'a-yl)-acetic acid 1,2-lactone (lR-antimer of 15, R 32 methyl).

PREPARATION 12 By following the method ofPreparation 8, Parts A and B, respectively, (Z'a-hydroxy-S 'B- benzyloxymethylcyclopent-l'a-yl)-acetic acid 1,2- lactone and (2 'oz-hydroxy-S 'B- methoxymethylcyclopent-la-yl)-acetic acid 1,2- lactone are converted into (2'a-hydroxy-5B- hydroxymethylcyclopent-la-yl)-acetic acid l,2-

lactone, which upon oxidation with chromium trioxidedipyridine complex, in accordance with the method of Part C of preparation 8, affords (2'a-hydroxy-5'B- formylcyclopent-l a-yl)-acetic acid l,2-lactone.

PREPARATION l2 By following the methods of Preparation 8, Parts A and B, respectively, 1'R-(2 'a-hydroxy-S ,8- benzyloxymethylcyclopent-l 'a-yl )-acetic acid l,2- lactone and l'R-(2oz-hydroxy-5'B- methoxymethylcyclopent-l a-yl)-acetic acid 1,2- lactone are converted into lR-(Z'oz-hydroxy-S'B- hydroxymethylcyclopent-l 'cx-yl )-acetic acid l ,2 la'ctone, which upon oxidation with chromium trioxidedipyridine complex, in accordance with the method of part C of Preparation 8, affords IR-(Z'a-hydroxy-SB- formylcyclopentl a-yl)-acetic acid l,2'-lactone.

PREPARATION 13 A. A solution of g. of dimethyl methylphosphonate in 670 ml. of anhydrous tetrahydrofuran is cooled to 78C. under an argon atmosphere. To the cold solution are added dropwise under stirring and under argon atmosphere, 495 ml. of a 0.1M solution of nbutyllithium in tetrahydrofuran, maintaining the temperature at 70C. When the addition is complete the reaction mixture is maintained under the same conditions for 10 additional minutes, a solution of 58 ml. of methyl caproate dissolved in 187 ml. of tetrahydrofuran is then carefully added, maintaining the temperature at 78C. The reaction mixture is stirred at 7 8C. for 2 hours followed by stirring for 4 hours at room temperature. The excess base is neutralized with acetic acid and the solvent is evaporated under high vacuo. The residue is dissolved in etherwater (I11, 950 ml. each), the ethereal phase is separated, washed with water and dried over magnesium sulfate. The ether is evaporated and the residue is purified by vacuum distillation, thus obtaining the pure dimethyl 2-oxoheptylphosphonate.

In a similar manner but using methyl n-butanoate, methyl n-pentanoate, ethyl nheptanoate, ethyl noctanoate and methyl n-undecanoate in place of methyl caproate, there are respectively obtained: di methyl 2-oxopentylphosphonate, dimethyl-Z-oxohexylphosphonate, dimethyl 2-oxo-octylphosphonate, dimethyl 2-oxononylphosphonate and dimethyl 2- oxododecylphosphonate.

B. To a suspension of 1.55 g. of sodium hydride (previously washed with pentane, under argon) in 355 ml. of dimethoxyethane freshly distilled from lithium aluminum hydride is added, under stirring and under an atmosphere of argon, a solution of 7.1 g. of dimethyl 2-oxoheptylphosphonate in ml. of dimethoxyethane. The reaction mixture is stirred for 30 minutes at room temperature and 10 g. of (2'a-hydroxy-4'a-pphenylbenzoyloxy-S 'B-formylcyclopent-l 'a-yl )-acetic acid l,2-lactone are added. The reaction mixture is stirred at room temperature for 2 hours further, it is then carefully neutralized with acetic acid (to pH 7) and evaporated to dryness under reduced pressure at a temperature below 30C. The solid residue is purified by chromatography on Florisil, using methylene chloride as eluant, to obtain [2a-hydroxy-4a-pphenylbenzoyloxy-S B-(3"-oxo-oct-1"(t)-en-l"-yl)- cyclopent-l 'a-yl]-acetic acid l,2-lactone (10, n 4) and a small amount of dimethyl 2-oxoheptylphosphonate.

Likewise but using dimethyl 2-oxopentylphosphonate, dimethyl 2-oxohexylphosphonate, dimethyl 2-oxooctylphosphonate, dimethyl 2-oxononylphosphonate and dimethyl 2-oxododecylphosphonate in place of dimethyl 2-oxoheptylphosphonate, there are produced:

[2 'a-hydroxy-4 'a-p-phenylbenzoyloxy-S 'B-( 3 oxohex-l "(t)-en-1-yl)-cyclopent-l 'a-yll-acetic acid l,2'-lactone,

[2'a-hydroxy-4'a-p-phenylbenzoyloxy-SB-(3- oxonon-l "(t)-en-l "-yl)-cyclopent-l 'a-yll-acetic acid l,2-lactone,

[2 'a-hydroxy-4'a-p-phenylbenzoyloxy-S 'B-( 3 oxodec-l (t)-en-l -yl)-cyclopent-l a-yl]-acetic acid l,2-lactone, and

[2'a-hydroxy-4a-p-phenylbenzoyloxy-5'B-(3"- oxotridec-l "(t)-enl -yl)-cyclopentl a-yl]- acetic acid l,2-lactone.

In a similar manner, (Za-hydroxy-S'B- formycyclopent-l a-yl)-acetic acid l,2'-lactone is converted into PREPARATION 13' In accordance with the method described in Part B of Preparation 13, lR-( 2'a-hydroxy-4a-pphenylbenzoyloxy-S 'B-formylcyclopent-l 'a-yl)-acetic acid l,2'-lactone is converted into l:R-[2a-hydroxy- 4a-p-phenylbenzoyloxy-5 ,8-( 3"-oxo-octl (t)-enl"-yl)-cyclopent-l 'a-yll-acetic acid 1,2-lactone (lR- antimer of 10, n 4).

Likewise but using dimethyl 2-oxopentylphosphonate, dimethyl 2-oxohexylphosphonate, dimethyl 2-0xooctylphosphonate, dimethyl 2-oxononylph0sphonate and dimethyl 2-oxododecylphosphonate in place of dimethyl 2-oxoheptylphosphonate, there are produced: lR-[2'a-hydroxy-4'a-p-phenylbenzoyloxy-S B-( 3"- oxohex-l "(t)-en-l "-yl)-cyclopent-l a-yl]-acetic acid l,2'-lactone.

lR-[2 'a-hydroxy-4'a-p-phenylbenzoyloxy-S 'B-( 3"- oxotridec-l "(t)-en-l -yl)-cyclopent-1 a-yl]- acetic acid l,2'-lactone, respectively.

In a similar manner, lR-(2a-hydroxy-5B- formylcyclopent-l'a-yl)-acetic acid l,2-lactone is converted into l'R-[Z'a-hydroxy-S',B-(3"-oxo-oct- 1(t)-en-l-yl)-cyclopent-la-yl]-acetic acid l,2'- lactone and lR-[2a-hydroxy-5B-(3"-oxo-dec-1 "(t)- en-l "-yl)-cyclopent-l a-yl]-acetic acid l,2'-lactone, using the appropriate reagent.

PREPARATION 14 To a stirred solution of 5.34 g. of [2'a-hydroxy-4'ap-phenylbenzoyloxy-S B-( 3 '-oxo-oct-1 "(t)-en-l -yl)- cyclopent-l 'a-yll-acetic acid l,2'-lactone in 36 ml. of dimethoxyethane freshly distilled from lithium aluminum hydride are added 9 ml. of zinc borohydride reagent in anhydrous dimethoxyethane. The reaction mixture is stirred for an additional hour at room temperature, and treated with a saturated solution of sodium bitartrate until the evolution of gas ceases. It is then diluted with methylene chloride, dried over magnesium sulfate and evaporated to dryness under vacuo at a temperature below 30C. to yield [2'a-hydroxy-4'a-pphenylbenzoyloxy-S ',B-( 3"a-hydroxyoct-l "(t)-en-l yl)-cyclopent-l 'a-yll-acetic acid 1,2'-lactone l l, R p-phenylbenzoyl; n 4) in mixture with the 3"B- hydroxy isomer.

The oily mixture is separated into the individual isomers by t.l.c. using a mixture of benzenemethylisobutyl ketone (2:1) as eluant.

Similarly the remaining 3"-oxo compounds obtained in Preparation l3 are converted into the respective 3"- hydroxy compounds, namely:

[2 'a-hydroxy-4'a-p-phenylbenzoyloxy-S 'B-( 3 'ahydroxyhex-l "(t)-en-l -yl)-cyclopent-l 'a-yl1- acetic acid l,2-lactone,

[2a-hydroxy-4'a-p-phenylbenzoyloxy-S 3-( 3 "ahydroxyhept-l "(t)-en-1 "-yl)-cyclopent-l a-yl]- acetic acid l,2'-lactone,

[2 'a-hydroxy-4'a-p-phenylbenzoyloxy-S 'B-( 3 'ahydroxynon-l "(t)-en-l "-yl)-cyclopent-l 'a-yl]- acetic acid l,2-lactone,

[2'a-hydroxy-4'a-p-phenylbenzoyloxy-S B-( 3 'ahydroxydec-l "(t)-en-l "-yl)-cyclopent l a-yl]- acetic acid l.2'-lactone,

[2 a-hydroxy-4'a-p-phenylbenzoyloxy-S /3-( 3 "ahydroxytridec-l (t)-en-l "-yl )-cyclopent-l 'a-yl]- acetic acid l,2-lactone,

[2'a-hydroxy-5 'B-( 3"a-hydroxyoct-l (t)-en-l yl)-cyclopent-la-yl]-acetic acid l,2'-lactone and [2a-hydroxy-5 '{3-( 3 "a-hydroxydec-l "(t)-en-l yl )-cyclopent-l 'a-yl]-acetic acid l,2-lactone,

in mixture with the corresponding 3",B-hydroxy isomers, which are separated by thin layer chromatography.

The zinc borohydride reagent is prepared from 0.025 mol of fused zinc chloride, 0.050 mol of sodium borohydride and ml. of dimethoxyethane, stirring the mixture for 16 hours and filtering the insoluble material under argon atmosphere.

PREPARATION 14' In accordance with the method of Preparation 14, l- 'R-[ 2 'a-hydroxy-4 'a-p-phenylbenzoyloxy-S 'B-( 3 oxo-oct-l "(t)-en-l "-yl)-cyclopent-l ayl]-acetic acid l,2'-lactone is converted into 1 R-[2a-hydroxy-4a-pphenylbenzoyloxy-S ,B-( 3 oz-hydroxyoct-l "(t)-en-l yl)-cyclopent-l a-yl]-acetic acid l,2'-lactone (lR- antimer of l l, R p-phenylbenzoyl); n 4) in mixture with the corresponding 3",B-hydroxy isomer.

Similarly the remaining 3"-oxo compounds obtained in Preparation 13 are converted into the respective 3"-hydroxy compounds, namely:

l'R-[ 2a-hydroxy-4'a-p-phenylbenzoyloxy-S 'B- (3 'a-hydroxyhex- 1(t)-en-'l "-yl)-cyclopent-l 'a-yl]-acetic acid l,2'- lactone,

(3 a-hydroxyhept-l "(t)en-l "-yl)-cyclopent-l 'ayllacetic acid l,2-lactone,

l 'R-[ 2 a-hydroxy-4'a-p-phenylbenzoyloxy-S 'B- (3"a-hydroxynonl "(t)-en-l "-yl)-cyclopent-l 'ayl]-acetic acid l,2-lactone,

l'R-[ 2ozhydroxy-4'oz-p-phnylbenzoyloxy-S 'B- (3"a-hydroxydec-1"(t)-en-l-yl)-cyclopent-layll-acetic acid l,2'-lactone,

1'R-[2 'a-hydroxy-4'a-p-phenylbenzoyloxy-S 'B- (3"a-hydroxytridec-l (t)-en-l "-yl)-cy'clopentl'a-yl]-acetic acid 1,2'-lactone,

1 "-yl)-cyclopent-1 'a-yl]-acetic acid l,2'-lactone and l'R-[2a-hydroxy-5 'B-( 3 "a-hydroxydec-l "(t)-enl"-yl)-cyclopent-l'a-yl]-acetic acid 1,2'-lactone, in mixture with the corresponding 3"B-hydroxy isomers, which are separated by thin layer chromatography.

PREPARATION 15 A solution of 3.7 g. of [2a-hydroxy-4'a-pphenylbenzoyloxy-5 'B-( 3 a-hydroxyoctl '(t)-en-l yl)-cyclopent-l a-yl]-acetic acid l,2-lactone in 37 ml. of anhydrous methanol is treated with 1.14 g. of anhydrous potassium carbonate, and the reaction mixture stirred for 2 /2 hours at room temperature. It is then cooled to C. and adjusted with ION aqueous hydrochloric acid until a pH of 2-3 is obtained. Ethyl acetate is added and the organinc solution washed with saturated sodium bicarbonate solution and saturated sodium potassium bitartrate solution, dried over magnesium sulfate and evaporated to dryness under vacuo. The residue is purified by filtration through a Florisil column (130 g.). The fractions eluted with methylene chloride-ethyl acetate give methyl pbiphenylcarboxylate and the fractions eluted with ethyl acetate yield [2,a,4'a-dihydroxy-5B-(3ahydroxyoct-l"(t)-en-l-yl)-cyclopent-1a-yl]-acetic acid l,2'-lactone (11, R H; n 4).

By the same method, from the corresponding 4'a-pphenylbenzoyloxy compounds there are obtained:

l-yl)-cyclopent-l 'a-yl]-acetic acid l,2-lactone,

en-l '-yl )-cyclopent-l a-yl ]-acetic acid 1,2- lactone,

l"-yl)-cyclopent-l a-yl -acetic acid l,2-lactone,

and

[2a,4a-dihydroxy-5 'B-(3 "a-hydroxytridec-l "(t)- en-l -yl)-cyclopent-1'a-yll-acetic acid l,2- lactone.

PREPARATION 15' By following the method of Preparation 15, l'R- [2 a-hydroxy-4a-p-phenylbenzoyloxy-S /3-( 3 ahydroxyoct-l "(t)-en-l "-yl)-cyclopent-l a-yl]-acetic acid l,2'-lactone is converted into lR-[2a,4'adihydroxy-5 'B-(3 a-hydroxyoct-l "(t)-enl "-yl)- cyclopent-la-yH-acetic acid l,2-lactone (lR- antimer of 11, R H; n 4).

By the same method, from the corresponding l'R.40a-p-phenylbenzoyloxy compounds of Preparation 14 there are obtained:

PREPARATION 16 To a solution of 2.3 g. of [2a,4a-dihydroxy- 5 ',8(3"a-hydroxyoct-l "(t)-en-l "-yl)-cyclopent-l '0:- yl]-acetic acid l,2'-lactone in 23 ml. of methylene chloride are added 2.3 ml. of freshly distilled dihydropyran and 23 mg. of anhydrous p-toluenesulfonic acid. The reaction mixture is stirred for 15 minutes at room temperature, a few drops of pyridine are added and diluted with ether. The ethereal solution is washed with ml. of 50 percent aqueous sodium chloride solution and then with saturated sodium chloride solution. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure, at approximately 0C., thus yielding [2'01- -hydroxy-4a-tetrahydropyranyloxy-S ,8-( 3 atet'rahydropyranyloxyoct-l "(t)-en-l "-yl )-cyclopentla-yll-acetic acid l,2'-lactone, (12, n 4) as an oil.

Similarly, the remaining compounds obtained in Preparation 15 are converted respectively into:

[2 'a-hydroxy-4a-tetrahydropyranyloxy-S B-( 3 "atetrahydropyranyloxyhex-1 (t)-en-l '-yl cyclopent-l a-yl]-acetic acid l,2'-lactone,

[2'a-hydroxy-4'a-tetrahydropyranyloxy-S B-( 3 'atetrahydropyranyloxyhept-l "(t)-en-l "-yl)- cyclopent-l 'a-yll-acetic acid l,2'-lactone,

[2 'a-hydroxy-4'a-tetrahydropyranyloxy-S 'B-( 3 'atetrahydropyranyloxynon-1(t)-en-l"yl)- cyclopent-l 'oz-yl]-acetic acid 1,2-lactone,

[2 'a-hydroxy-4'a-tetrahydropyranyloxy-S 'B-( 3 '21- tetrahydropyranyloxydec-l "(t)-en-l "-yl)- cyclopent-l a-yl]-acetic acid l,2'-lactone and [2a-hydroxy-4'a-tetrahydropyranyloxy-5 'B-( 3 'atetrahydropyranyloxytridec l (t)-en-l "-yl cyclopent-1a-yl1-acetic acid l,2-lactone.

In a similar manner, [2'a-hydroxy-5'B-(3"ahydroxyoct-l "(t)-en-l '-yl)-cyclopentl 'a-yl]-acetic acid 1,2 -lactone and [2'a-hydroxy-5 B-( 3 '01- hydroxydec-l "(t)-en-l "-yl)-cyclopent-l 'a-ylI-acetic acid l,2'-lactone are converted respectively into [2'01- hydroxy-S ',B-( 3 'a-tetrahydropyranyloxyoct-1 "(t)-enl"-yl)-cyclopent-la-yll-acetic acid l,2'-lactone and [2 'a-hydroxy-S B-( 3 a-tetrahydropyranyloxydecl "(t)-en-1-yl)-cyclopent-1 a-yl]-acetic acid lactone.

PREPARATION 16' By following the method of Preparation 16. lR- [2a,4'a-dihydroxy-5 'B-( 3"a-hydroxyoct-l "(t)-enl"-yl)-cyclopent-la-yl]-acetic acid l,2'-lactone is converted into 1'R-[2'B-hydroxy-4'B- tetrahydropyranyloxy-S 'B-( 3 'a- 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF RACEMIC MIXTURES AND 8R-ANTIMERS OF THOSE REPRESENTED BY THE FORMUULAS:
 1. A compound selected from the group consisting of racemic mixtures and 8R-antimers of those represented by the formulas:
 2. A compound according to claim 1 wherein said compound is a racemic mixture.
 3. A compound according to claim 2 wherein R1, R2 and R3 are hydroxy and R, R4 and R5 are hydrogen.
 4. A compound according to claim 2 wherein R, R1R4 and R5 are hydrogen and R2 and R3 are hydroxy.
 5. A compound according to claim 2 wherein R is methyl, ethyl or propyl, R1, R2 and R3 are hydroxy and R4 and R5 are hydrogen.
 6. A compound according to claim 2 wherein R is methyl, ethyl or propyl, R2 and R3 are hydroxy and R1, R4 and R5 are hydrogen.
 7. A compound according to claim 2 wherein R5 is methyl, ethyl or propyl, R1, R2 and R3 are hydroxy and R and R4 are hydrogen.
 8. A compound according to claim 2 wherein R5 is methyl, ethyl or propyl, R2 and R3 are hydroxy and R, R1 and R4 are hydrogen.
 9. A compound according to claim 2 wherein each of R and R5 are methyl, ethyl or propyl, R1, R2 and R3 are hydroxy and R4 is hydrogen.
 10. A compound according to claim 2 wherein each of R and R5 are methyl, ethyl or propyl, R2 and R3 are hydroxy and R1 and R4 are hydrogen.
 11. A compound according to claim 2 wherein n is
 4. 12. A compound according to claim 2 formula (A) wherein R, R4 and R5 are hydrogen, R1 and R2 are hydroxy and n is 4, 9-keto-11 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic pharmaceutically acceptable salts thereof.
 13. A compound according to claim 2 formula (A) wherein R and R5 are hydrogen, R4 is methyl, R1 and R2 are hydroxy, and n is 4, 9-keto-11 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid methyl ester.
 14. A compound according to claim 2 formula (A) wherein R, R1, R4 and R5 are hydrogen, R2 is hydRoxy and n is 4, 9-keto-15 Alpha -hydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 15. A compound according to claim 2 formula (A) wherein R is methyl, R4 and R5 are hydrogen, R1 and R2 are hydroxy and n is 4, 4-methyl-9-keto-11 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 16. A compound according to claim 2 formula (A) wherein R is methyl, R1, R4 and R5 are hydrogen, R2 is hydroxy and n is 4, 4-methyl-9-keto-15 Alpha -hydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 17. A compound according to claim 2 formula (A) wherein R and R4 are hydrogen, R5 is methyl, R1 and R2 are hydroxy, and n is 4, 6-methyl-9-keto-11 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 18. A compound according to claim 2 formula (A) wherein R, R1 and R4 are hydrogen, R5 is methyl, R2 is hydroxy and n is 4, 6-methyl-9-keto-15 Alpha -hydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 19. A compound according to claim 2 formula (A) wherein R and R5 are methyl, R1 and R2 are hydroxy, R4 is hydrogen and n is 4, 4, 6-dimethyl-9-keto-11 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 20. A compound according to claim 2 formula (A) wherein R and R5 are methyl, R2 is hydroxy, R1 and R4 are hydrogen and n is 4, 4, 6-dimethyl-9-keto-15 Alpha -hydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 21. A compound according to claim 2 formula (A) wherein R, R1, R4 and R5 are hydrogen, R2 is hydroxy and n is 6, 9-keto-15 Alpha -hydroxy-20-ethylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 22. A compound according to claim 2 formula (B) wherein R, R4 and R5 are hydrogen, R1, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 4, 9 Alpha ,11 Alpha , 15 Alpha -trihydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 23. A compound according to claim 2 formula (B) wherein R and R5 are hydrogen, R4 is methyl, R1, R2 and R3 are hydroxy, the wavy line indicates the Alpha configuration and n is 4, 9 Alpha ,11 Alpha ,15 Alpha -trihydroxyprosta-4,5,13-trans-trienoic acid methyl ester.
 24. A compound according to claim 2 formula (B) wherein R, R4 and R5 are hydrogen, R1, R2 and R3 are hydroxy, the wavy line indicates the Beta -configuration and n is 4, 9 Beta ,11 Alpha , 15 Alpha -trihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 25. A compound according to claim 2 formula (B) wherein R, R4 and R5 are hydrogen, R1, R2 and R3 are hydroxy, the wavy lines indicates the Beta -configuration and n is 6, 9 Beta ,11 Alpha , 15 Alpha -trihydroxy-20-ethylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 26. A compound according to claim 2 formula (B) wherein R, R1, R4 and R5 are hydrogen, R2 and R3 are hydroxy the wavy line indiCates the Alpha -configuration and n is 4, 9 Alpha ,15 Alpha -diydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 27. A compound according to claim 2 formula (B) wherein R, R1, R4 and R5 are hydrogen, R2 and R3 are hydroxy, the wavy line indicates the Beta -configuration and n is 4, 9 Beta ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 28. A compound according to claim 2 formula (B) wherein R, R1, R4 and R5 are hydrogen, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 6, 9 Alpha ,15 Alpha -dihydroxy-20-ethylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 29. A compound according to claim 2 formula (B) wherein R, R1, R4 and R5 are hydrogen, R2 and R3 are hydroxy, the wavy line indicates the Beta -configuration and n is 6, 9 Beta ,15 Alpha -dihydroxy-20-ethylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 30. A compound according to claim 2 formula (B) wherein R is methyl, R4 and R5 are hydrogen, R1, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 4, 4-methyl-9 Alpha ,11 Alpha ,15 Alpha -trihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 31. A compound according to claim 2 formula (B) wherein R is methyl, R1, R4 and R5 are hydrogen, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 4, 4-methyl-9 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 32. A compound according to claim 2 formula (B) wherein R5 is methyl, R and R4 are hydrogen, R1, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 4, 6-methyl-9 Alpha ,11 Alpha ,15 Alpha -trihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 33. A compound according to claim 2 formula (B) wherein R5 is methyl, R, R1 and R4 are hydrogen, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 4, 6-methyl-9 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 34. A compound according to claim 2 formula (B) wherein R and R5 are methyl, R1, R2 and R3are hydroxy, R4 is hydrogen, the wavy line indicates the Alpha -configuration and n is 4, 4,6-dimethyl-9 Alpha ,11 Alpha ,15 Alpha -trihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 35. A compound according to claim 2 formula (B) wherein R and R5 are methyl, R2 and R3 are hydroxy, R1 and R4 are hydrogen, the wavy line indicates the Alpha -configuration and n is 4, 4,6-dimethyl-9 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 36. A compound according to claim 2 formulas (C) and (D) wherein the hydroxy group at C-15 is in the Alpha -configuration and the alkyl group at said position is in the Beta -configuration.
 37. A compound according to claim 2, formulas (C) and (D) wherein the hydroxy group at C-15 is in the Beta -configuration and the alkyl group at said position is in the Alpha -configuration.
 38. A compound according to claim 2, formula (C) whereiN R, R4 and R5 are hydrogen, R1 is hydroxy, R6 is Beta -methyl and n is 4, 9-keto-11 Alpha ,15 Alpha -dihydroxy-15 Beta -methylprosta-4, 5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 39. A compound according to claim 2, formula (C) wherein R, R1, R4 and R5 are hydrogen, R6 is Beta -methyl and n is 4, 9-keto-15 Alpha -hydroxy-15 Beta -methylprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 40. A compound according to claim 2, formula (D) wherein R, R4 and R5 are hydrogen, R1 is hydrogen, R1 is hydroxy, R3 is Alpha -hydroxy, R6 is Beta -methyl and n is 4, 9 Alpha ,11 Alpha ,15 Alpha -trihydroxy-15 Beta -methylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 41. A compound according to claim 2 formula (D) wherein R, R1, R4 and R5 are hydrogen, R3 is Alpha -hydroxy, R6 is Beta -methyl and n is 4, 9 Alpha ,15 Alpha -dihydroxy-15 Beta -methylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 42. A compound according to claim 1 wherein said compound is a 8R-antimer.
 43. A compound according to claim 42 wherein R1, R2 and R3 are hydroxy and R, R4 and R5 are hydrogen.
 44. A compound according to claim 42 wherein R, R1, R4 and R5 are hydrogen and R2 and R3 are hydroxy.
 45. A compound according to claim 42 wherein R is methyl, ethyl or propyl, R1, R2 and R3 are hydroxy and R4 and R5 are hydrogen.
 46. A compound according to claim 42 wherein R is methyl, ethyl or propyl, R2 and R3 are hydroxy and R1, R4 and R5 are hydrogen.
 47. A compound according to claim 42 wherein R5 is methyl, ethyl or propyl, R1, R2 and R3 are hydroxy and R and R4 are hydrogen.
 48. A compound according to claim 42 wherein R5 is methyl, ethyl or propyl, R2 and R3 are hydroxy and R, R1 and R4 are hydrogen.
 49. A compound according to claim 42 wherein each of R and R5 are methyl, ethyl or propyl, R1, R2 and R3 are hydroxy and R4 is hydrogen.
 50. A compound according to claim 42 wherein each of R and R5 are methyl, ethyl or propyl, R2 and R3 are hydroxy and R1 and R4 are hydrogen.
 51. A compound according to claim 42 wherein n is
 4. 52. A compound according to claim 42 formula (A) wherein R, R4 and R5 are hydrogen, R1 and R2 are hydroxy and n is 4, 8R-9-keto-11 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic pharmaceutically acceptable salts thereof.
 53. A compound according to claim 42 formula (A) wherein R and R5 are hydrogen, R4 is methyl, R1 and R2 are hydroxy, and n is 4, 8R-9-keto-11 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid methyl ester.
 54. A compound according to claim 42 formula (A) wherein R, R1, R4 and R5 are hydrogen, R2 is hydroxy and n is 4, 8R-9-keto-15 Alpha -hydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 55. A compound according to claim 42 formula (A) wherein R is methyl, R4 and R5 are hydrogen, R1 and R2 are hydroxy and n is 4, 8R-4-methyl-9-keto-11 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic aciD the non-toxic, pharmaceutically acceptable salts thereof.
 56. A compound according to claim 42 formula (A) wherein R is methyl, R1, R4 and R5 are hydrogen, R2 is hydroxy and n is 4, 8R-4-methyl-9-keto-15 Alpha -hydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 57. A compound according to claim 42 formula (A) wherein R and R4 are hydrogen, R5 is methyl, R1 and R2 are hydroxy, and n is 4, 8R-6-methyl-9-keto-11 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 58. A compound according to claim 42 formula (A) wherein R, R1 and R4 are hydrogen, R5 is methyl, R2 is hydroxy n is 4, 8R-6-methyl-9-keto-15 Alpha -hydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 59. A compound according to claim 42 formula (A) wherein R and R5 are methyl, R1 and R2 are hydroxy, R4 is hydrogen and n is 4, 8R-4,6-dimethyl-9-keto-11 Alpha ,15 Alpha -dihydroxyprosta-4,5, 13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 60. A compound according to claim 42 formula (A) wherein R and R5 are methyl, R2 is hydroxy, R1 and R4 are hydrogen and n is 4, 8R-4,6-dimethyl-9-keto-15 Alpha -hydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 61. A compound according to claim 42 formula (A) wherein R, R4 and R5 are hydrogen, R1 and R2 are hydroxy, and n is 6, 8R-9-keto-11 Alpha ,15 Alpha -dihydroxy-20-ethylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 62. A compound according to claim 42 formula (A) wherein R, R1, R4 and R5 are hydrogen, R2 is hydroxy and n is 6, 8R-9-keto-15 Alpha -hydroxy-20-ethylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 63. A compound according to claim 42 formula (B) wherein R, R4 and R5 are hydrogen, R1, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 4, 8R-9 Alpha ,11 Alpha ,15 Alpha -trihydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 64. A compound according to claim 42 formula (B) wherein R and R5 are hydrogen, R4 is methyl, R1, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 4, 8R-9 Alpha ,11 Alpha ,15 Alpha -trihydroxyprosta-4,5,13-trans-trienoic acid methyl ester.
 65. A compound according to claim 42, formula (B) wherein R, R4 and R5 are hydrogen, R1, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 6, 8R-9 Alpha ,11 Alpha ,15 Alpha -trihydroxy-20-ethylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 66. A compound according to claim 42 formula (B) wherein R, R 4 and R5 are hydrogen, R1, R2 and R3 are hydroxy, the wavy line indicates the Beta -configuration and n is 4, 8R-9 Beta ,11 Alpha ,15 Alpha -trihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 67. A compound according to claim 42 formula (B) wherein R, R4 and R5 are hydrogen, R1, R2 and R3 are hydroxy, The wavy line indicates the Beta -configuration and n is 6, 8R-9 Beta ,11 Alpha ,15 Alpha -trihydroxy-20-ethylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 68. A compound according to claim 42 formula (B) wherein R, R1, R4 and R5 are hydrogen, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 4, 8R-9 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 69. A compound according to claim 42 formula (B) wherein R, R1, R4 and R5 are hydrogen, R2 and R3 are hydroxy, the wavy line indicates the Beta -configuration and n is 4, 8R-9 Beta ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 70. A compound according to claim 42 formula (B) wherein R, R1, R4 and R5 are hydrogen, R2 and R3 are hydroxy, the wavy line indicate the Alpha -configuration and n is 6, 8R-9 Alpha ,15 Alpha -dihydroxy-20-ethylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 71. A compound according to claim 42 formula (B) wherein R, R1, R4 and R5 are hydrogen, R2 and R3 are hydroxy, the wavy line indicates the Beta -configuration and n is 6, 8R-9 Beta ,15 Alpha -dihydroxy-20-ethylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 72. A compound according to claim 42 formula (B) wherein R is methyl, R4 and R5 are hydrogen, R1, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 4, 8R-4-methyl-9 Alpha ,11 Alpha ,15 Alpha -trihydroxyprosta-4,5,13-trans-trienoic acid the non-toxic, pharmaceutically acceptable salts thereof.
 73. A compound according to claim 43 formula (B) wherein R is methyl, R1, R4 and R5 are hydrogen, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 4, 8R-4-methyl-9 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 74. A compound according to claim 42 formula (B) wherein R5 is methyl, R and R4 are hydrogen, R1, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 4, 8R-6-methyl-9 Alpha ,,15 Alpha -trihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 75. A compound according to claim 42 formula (B) wherein R5 is methyl, R, R1 and R4 are hydrogen, R2 and R3 are hydroxy, the wavy line indicates the Alpha -configuration and n is 4, 8R-6-methyl-9 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 76. A compound according to claim 42 formula (B) wherein R and R5 are methyl, R1, R2 and R3 are hydroxy, R4 is hydrogen, the wavy line indicates the Alpha -configuration and n is 4, 8R-4,6-dimethyl-9 Alpha ,11 Alpha ,15 Alpha -trihydroxyprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 77. A compound according to claim 42 formula (B) wherein R and R5 are methyl, R2 and R3 are hydroxy, R1 and R4 are hydrogen, the wavy line indicates the Alpha -configuration and n is 4, 8R-4,6-dimethyl-9 Alpha ,15 Alpha -dihydroxyprosta-4,5,13-trans-trienoic acid and the noN-toxic, pharmaceutically acceptable salts thereof.
 78. A compound according to claim 42 formulas (C) and (D) wherein the hydroxy group at C-15 is in the Alpha -configuration and the alkyl group at said position is in the Beta -configuration.
 79. A compound according to claim 42, formulas (C) and (D) wherein the hydroxy group at C-15 is in the Beta -configuration and the alkyl group at said position is in the Alpha -configuration.
 80. A compound according to claim 42, formula (C) wherein R, R4 and R5 are hydrogen, R1 is hydroxy, R6 is Beta -methyl and n is 4, 8-R9-keto-11 Alpha ,15 Alpha -dihydroxy-1562 -methylprosta-4, 5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 81. A compound according to claim 42, formula (C) wherein R, R1, R4 and R5 are hydrogen, R6 is Beta -methyl and n is 4, 8R-9-keto-15 Alpha -hydroxy-15 Beta -methylprosta-4,5,13-trans-trienoic acid, and the non-toxic, pharmaceutically acceptable salts thereof.
 82. A compound according to claim 42, formula (D) wherein R, R4 and R5 are hydrogen, R1 is hydroxy, R3 is Alpha -hydroxy, R6 is Beta -methyl and n is 4, 8R-9 Alpha ,11 Alpha ,15 Alpha -trihydroxy-15 Beta -methylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 83. A compound according to claim 42 formula (D) wherein R, R1, R4 and R5 are hydrogen, R3 is a Alpha -hydroxy, R6 is Beta -methyl and n is 4, 8R-9 Alpha ,15 Alpha -dihydroxy-15 Beta -methylprosta-4,5,13-trans-trienoic acid and the non-toxic, pharmaceutically acceptable salts thereof.
 84. A compound according to claim 2 formula (D) wherein R and R5 are hydrogen, R1 is hydroxy, R3 is Alpha -hydroxy, R4 and R6 are methyl and n is 4,9 Alpha ,11 Alpha ,15 -trihydroxy-15 -methylprosta-4,5,13-trans-trienoic acid methyl ester.
 85. A compound according to claim 2 formula (D) wherein R and R5 are hydrogen, R1 is hydroxy, R3 is Alpha -hydroxy, R4 is methyl, R6 is Beta -methyl and n is 4,9 Alpha ,11 Alpha ,15 Alpha -trihydroxy-15 Beta -methylprosta-4,5,13-trans-trienoic acid methyl ester. 